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Enhanced Retinal Ganglion Cell Survival in Glaucoma by Hypoxic Postconditioning After Disease Onset.

ABSTRACT: The neuroprotective efficacy of adaptive epigenetics, wherein beneficial gene expression changes are induced by nonharmful "conditioning" stimuli, is now well established in several acute, preclinical central nervous system injury models. Recently, in a mouse model of glaucoma, we demonstrated retinal ganglion cell (RGC) protection by repetitively "preconditioning" with hypoxia prior to disease onset, indicating an epigenetic approach may also yield benefits in chronic neurodegenerative disease. Herein, we determined whether presenting the repetitive hypoxic stimulus after disease initiation [repetitive hypoxic "postconditioning" (RH-Post)] could afford similar functional and morphologic protection against glaucomatous RGC injury. Chronic elevations in intraocular pressure (IOP) were induced unilaterally in adult male C57BL/6 mice by episcleral vein ligation. Mice were randomized to an RH-Post [1 h of systemic hypoxia (11% oxygen) every other day, starting 4 days after IOP elevation] or an untreated control group. After 3 weeks of experimental glaucoma, the 21-27% reduction and 5-25% prolongation in flash visual-evoked potential amplitudes and latencies, respectively, and the 30% impairment in visual acuity were robustly improved in RH-Post-treated mice, as was the 17% loss in RGC soma number and 20% reduction in axon integrity. These protective effects were observed without RH-Post affecting IOP. The present findings demonstrate that functional and morphologic protection of RGCs can be realized by stimulating epigenetic responses during the early stages of disease, and thus constitute a new conceptual approach to glaucoma therapeutics.

SUBMITTER: Gidday JM

PROVIDER: S-EPMC4404439 | biostudies-literature | 2015 Apr

REPOSITORIES: biostudies-literature

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Enhanced Retinal Ganglion Cell Survival in Glaucoma by Hypoxic Postconditioning After Disease Onset.

Gidday Jeffrey M JM Zhang Lihong L Chiang Chia-Wen CW Zhu Yanli Y

Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics 20150401 2

The neuroprotective efficacy of adaptive epigenetics, wherein beneficial gene expression changes are induced by nonharmful "conditioning" stimuli, is now well established in several acute, preclinical central nervous system injury models. Recently, in a mouse model of glaucoma, we demonstrated retinal ganglion cell (RGC) protection by repetitively "preconditioning" with hypoxia prior to disease onset, indicating an epigenetic approach may also yield benefits in chronic neurodegenerative disease. ...[more]

PMID: 25549850

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Project description:The BCL-2 (B-cell lymphoma-2) family of proteins contributes to mitochondrial-based apoptosis in models of neurodegeneration, including glaucomatous optic neuropathy (glaucoma), which degrades the retinal ganglion cell (RGC) axonal projection to the visual brain. Glaucoma is commonly associated with increased sensitivity to intraocular pressure (IOP) and involves a proximal program that leads to RGC dendritic pruning and a distal program that underlies axonopathy in the optic projection. While genetic deletion of the Bcl2-associated X protein (Bax-/-) prolongs RGC body survival in models of glaucoma and optic nerve trauma, axonopathy persists, thus raising the question of whether dendrites and the RGC light response are protected. Here, we used an inducible model of glaucoma in Bax-/- mice to determine if Bax contributes to RGC dendritic degeneration. We performed whole-cell recordings and dye filling in RGCs signaling light onset (αON-Sustained) and offset (αOFF-Sustained). We recovered RGC dendritic morphologies by confocal microscopy and analyzed dendritic arbor complexity and size. Additionally, we assessed RGC axon function by measuring anterograde axon transport of cholera toxin subunit B to the superior colliculus and behavioral spatial frequency threshold (i.e., spatial acuity). We found 1 month of IOP elevation did not cause significant RGC death in either WT or Bax-/- retinas. However, IOP elevation reduced dendritic arbor complexity of WT αON-Sustained and αOFF-Sustained RGCs. In the absence of Bax, αON- and αOFF-Sustained RGC dendritic arbors remained intact following IOP elevation. In addition to dendrites, neuroprotection by Bax-/- generalized to αON-and αOFF-Sustained RGC light- and current-evoked responses. Both anterograde axon transport and spatial acuity declined during IOP elevation in WT and Bax-/- mice. Collectively, our results indicate Bax contributes to RGC dendritic degeneration and distinguishes the proximal and distal neurodegenerative programs involved during the progression of glaucoma.

Project description:PurposeThe purpose of this study was to identify a robust, representative region of interest (ROI) for studies of retinal ganglion cell (RGC) soma loss in feline congenital glaucoma (FCG), a spontaneous, large-eyed glaucoma model.MethodsSeven FCG and three wild-type (wt) eyes were collected from 10 adult cats of both sexes. Eyes enucleated postmortem were immediately fixed overnight in 4% paraformaldehyde and then stored in 0.1 M PBS at 4 °C. The retinas were wholemounted, Nissl stained with cresyl violet, and imaged using light microscopy. Somas of RGCs were manually identified according to long-established morphological criteria and quantified using a semiautomated method; their coordinates were used to create density maps and plots of the retinal topography. The RGC axon counts for the corresponding eyes were obtained from glutaraldehyde-fixed, resin-embedded optic nerve cross-sections stained with 0.1% p-phenylenediamine (PPD) using a semiautomated counting method. Correlations between total optic nerve axons and RGC soma counts were assessed by linear regression. A k-means cluster algorithm was used to identify a retinal ROI, with further definition using a probability density algorithm.ResultsInterindividual variability in RGC total soma counts was more pronounced in FCG cats (mean = 83,244, range: 0-155,074) than in wt cats (mean = 117,045, range: 97,373-132,972). In general, RGC soma counts were lower in FCG cats than they were in wt cats. RGC axon counts in the optic nerve cross-sections were lower than, but strongly correlated to, the total RGC soma count across all cats (in wt and FCG retinas; R2 = 0.88) and solely FCG eyes (R2 = 0.92). The k-means cluster algorithm indicated a region of the greatest mean difference between the normal wt retinas and FCG-affected retinas within the temporal retina, incorporating the region of the area centralis.ConclusionsAs in other species, RGC soma count and topography are heterogeneous between individual cats, but we identified an ROI in the temporal retina for future studies of RGC soma loss or preservation in a large-eyed model of congenital glaucoma. Many of the methods refined and established to facilitate studies in this FCG model will be broadly applicable to studies in other large-eyed models.

Dataset Information

Enhanced Retinal Ganglion Cell Survival in Glaucoma by Hypoxic Postconditioning After Disease Onset.

Publications

Enhanced Retinal Ganglion Cell Survival in Glaucoma by Hypoxic Postconditioning After Disease Onset.

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